Aloha, my name is Kekoa. I was born and raised in Mililani, Oʻahu, Hawaiʻi. My life’s mission has been to return home to the islands to provide high quality cancer care to the communities that raised me. I completed my PhD at Johns Hopkins School of Medicine and MD at Mayo Clinic Alix School of Medicine. I am currently a resident physician in the Department of Radiation Oncology at Stanford where I receive training in how to treat a variety of cancers. My research interests include Pacific Islander health disparities, "AAPI" health data disaggregation, access to cancer care disparities, oligometastatic prostate cancer, and the impact of cancer healthcare costs have on survival outcomes. I welcome interdisciplinary collaborations to advance the health of our underserved Pacific Islander communities.
Honors & Awards
Stanford Cancer Institute - Cancer Innovation Award, Stanford Medicine (2022)
ASCO Journals Editorial Fellowship, ASCO (2022)
Tobacco Related Disease Research Program Research Grant Award, TRDRP (2022)
Cures Within Reach Repurposing Research Grant Award, Cures Within Reach Foundation (2021)
Scholar-In-Training Award, AACR (2021)
Conquer Cancer Merit Award - ASCO Quality Care Symposium, ASCO Conquer Cancer Foundation (2021)
SoMe Award (Most Influential Article in Issue), European Urology Oncology (2021)
Annual Meeting Abstract Achievement Award, American Society of Hematology (2018)
National Alumni Council Scholarship Award, National Medical Fellowships (2018)
Medical Student Rotation Award, ASCO Conquer Cancer Foundation (2018)
Kamehameha Schools c/o 1960 Scholarship and c/o 1962 Scholarship Awards, Princess Pauahi Foundation (2018)
Minority Medical Student Award Program Award, American Society of Hematology (2018)
Hugh J. Andersen Memorial Scholarship Award, National Medical Fellowships (2018)
Helen N. & Harold B. Shapira Heart Medical Scholarship, American Heart Association (2017)
Minority Summer Fellowship Award - Clinical Fellow, ASTRO (2017)
Mayo Clinic Division of Hematology and Division of Oncology Medical Student Research Award, Mayo Clini (2017)
Takeda Oncology Scholar in Training Award, AACR (2016)
Martin Luther King, Jr. Award for Community Service, Johns Hopkins University and Johns Hopkins Health System (2015)
Thermo Fisher Scientific Antibody Scholarship, Thermo Fisher Scientific (2015)
Minority Scholar in Cancer Research Award, AACR (2015)
F31 Predoctoral Fellowship National Research Service Award (NRSA) - F31CA189588, NIH/NCI (2014)
Models and Mechanisms of Cancer Graduate Student Travel Award, Cold Spring Harbor Laboratories (2014)
Valedictorian/Commencement Speaker, Fairfield University (2012)
Doctor of Philosophy, Johns Hopkins University (2020)
PhD, Johns Hopkins University School of Medicine, Cellular and Molecular Medicine (2016)
MD, Mayo Clinic Alix School of Medicine, Science of Health Care Delivery (2020)
Quynh-Thu Le, Postdoctoral Faculty Sponsor
Diversity and Identity
Race and Ethnicity
- Attrition of Indigenous Medical Students Requires Swift Institutional Response. JAMA internal medicine 2022
- Mental Health and Substance Use Among US Homeless Adolescents. JAMA 2022; 328 (9): 889-890
Mental Health and Substance Use Among US Homeless Adolescents RESPONSE
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2022; 328 (9): 889-890
View details for Web of Science ID 000855171700028
Longitudinal Analysis of a Social Media Campaign to Increase Awareness and Engagement Among Radiation Oncologists for Black History Month (BHM)
LIPPINCOTT WILLIAMS & WILKINS. 2022: S46-S47
View details for Web of Science ID 000847787800099
- Outcomes of patients with stage I-II Hodgkin lymphoma who had uniform pre-treatment staging with PET/CT and treatment with limited field radiation therapy after chemotherapy. Blood cancer journal 2022; 12 (8): 121
Disparities in Survival and Comorbidity Burden Between Asian and Native Hawaiian and Other Pacific Islander Patients With Cancer.
JAMA network open
2022; 5 (8): e2226327
Improper aggregation of Native Hawaiian and other Pacific Islander individuals with Asian individuals can mask Native Hawaiian and other Pacific Islander patient outcomes. A comprehensive assessment of cancer disparities comparing Asian with Native Hawaiian and other Pacific Islander populations is lacking.To compare comorbidity burden and survival among East Asian, Native Hawaiian and other Pacific Islander, South Asian, and Southeast Asian individuals with non-Hispanic White individuals with cancer.This retrospective cohort study used a national hospital-based oncology database enriched with Native Hawaiian and other Pacific Islander and Asian populations. Asian, Native Hawaiian and other Pacific Islander, and White individuals diagnosed with the most common cancers who received treatment from January 1, 2004, to December 31, 2017, were included. Patients younger than 18 years, without pathologic confirmation of cancer, or with metastatic disease were excluded. Data were analyzed from January to May 2022.The primary end points were comorbidity burden by Charlson-Deyo Comorbidity Index and overall survival (OS).In total, 5 955 550 patients were assessed, including 60 047 East Asian, 11 512 Native Hawaiian and other Pacific Islander, 25 966 South Asian, 42 815 Southeast Asian, and 5 815 210 White patients. The median (IQR) age was 65 (56-74) years, median (IQR) follow-up was 58 (30-96) months, and 3 384 960 (57%) were women. Patients were predominantly from metropolitan areas (4 834 457 patients [84%]) and the Southern United States (1 987 506 patients [34%]), with above median education (3 576 460 patients [65%]), and without comorbidities (4 603 386 patients [77%]). Cancers included breast (1 895 351 patients [32%]), prostate (948 583 patients [16%]), kidney or bladder (689 187 patients [12%]), lung (665 622 patients [11%]), colorectal (659 165 patients [11%]), melanoma (459 904 patients [8%]), endometrial (307 401 patients [5%]), lymphoma (245 003 patients [4%]), and oral cavity (85 334 patients [1%]) malignant neoplasms. Native Hawaiian and other Pacific Islander patients had the highest comorbidity burden (adjusted odds ratio [aOR], 1.70; 95% CI, 1.47-1.94) compared with Asian and White groups. Asian patients had superior OS compared with White patients for most cancers; only Southeast Asian patients with lymphoma had inferior survival (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.16-1.37). In contrast, Native Hawaiian and other Pacific Islander patients demonstrated inferior OS compared with Asian and White patients for oral cavity cancer (aHR, 1.56; 95% CI, 1.14-2.13), lymphoma (aHR, 1.35; 95% CI, 1.11-1.63), endometrial cancer (aHR, 1.30; 95% CI, 1.12-1.50), prostate cancer (aHR, 1.29; 95% CI, 1.14-1.46), and breast cancer (aHR, 1.09; 95% CI, 1.00-1.18). No cancers among Native Hawaiian and other Pacific Islander patients had superior OS compared with White patients.In this cohort study, compared with White patients with the most common cancers, Asian patients had superior survival outcomes while Native Hawaiian and other Pacific Islander patients had inferior survival outcomes. Native Hawaiian and other Pacific Islander patients had significantly greater comorbidity burden compared with Asian and White patients, but this alone did not explain the poor survival outcomes. These results support the disaggregation of these groups in cancer studies.
View details for DOI 10.1001/jamanetworkopen.2022.26327
View details for PubMedID 35960520
- Do no harm: A call to action on COVID-19 and mask requirements. Cancer 2022
- Data aggregation hides Pacific Islander health disparities. Lancet (London, England) 2022
Disaggregation of Asian American and Pacific Islander Women With Stage 0-II Breast Cancer Unmasks Disparities in Survival and Surgery-to-Radiation Intervals: A National Cancer Database Analysis From 2004 to 2017.
JCO oncology practice
Aggregation of Asian Americans (AAs) with Native Hawaiians and Other Pacific Islanders (NHPIs) masks significant health disparities. We evaluated overall survival (OS) and surgery-to-radiation intervals (STRIs) among AA and NHPI women with early-stage breast cancer.This National Cancer Database study included women with stage 0-II breast cancer diagnosed between 2004 and 2017. STRI was defined as days from surgery to radiation. Patients were stratified by adjuvant treatment. AAs were disaggregated into geographically relevant subpopulations: East, South, and Southeast Asians. Kaplan-Meier estimates and log-rank tests assessed survival. Cox proportional hazard and linear regression were adjusted for clinical and sociodemographic factors.In total, 578,927 women were included (median age 61 years, median follow-up 65 months, and 10-year OS 83%). AA and NHPI 10-year OS was 91% overall; subpopulation 10-year OS was 92% for East Asian, 90% for South Asian, 90% for Southeast Asian, and 83% for NHPI. On multivariable analysis, compared with non-Hispanic White, NHPI women had worse survival (adjusted hazard ratio [aHR] = 1.38; 95% CI, 1.09 to 1.77); all AA subpopulations had improved survival: East Asian (aHR = 0.57; 95% CI, 0.48 to 0.69), South Asian (aHR = 0.66; 95% CI, 0.51 to 0.84), and Southeast Asian (aHR = 0.78; 95% CI, 0.65 to 0.94). The AA and NHPI median STRI for was 73 days overall; the disaggregated median STRI was 68 days for East Asian, 80 days for South Asian, 77 days for Southeast Asians, and 81 days for NHPI. On adjusted analysis, compared with non-Hispanic White, Southeast Asians and NHPI had longer STRI by 6.6 (95% CI, 4.3 to 8.9) and 10.0 (95% CI, 5.8 to 14) days, respectively.Breast cancer disparities exist among disaggregated AA and NHPI subpopulations. Data disaggregation insights may lead to interventions to overcome these disparities, such as optimizing time-to-treatment for select populations.
View details for DOI 10.1200/OP.22.00001
View details for PubMedID 35594493
Low-Cost, Multi-Center, Longitudinal Remote Training Improves Confidence in Head and Neck Contouring
ELSEVIER SCIENCE INC. 2021: E348
View details for Web of Science ID 000715803800707
The Impact of COVID-19 on Radiation Oncology Residency Applicant Away Rotations, Interviews, and Rank Lists: A Comparison Between the 2020 Match and 2021 Match.
Advances in radiation oncology
Background: The COVID-19 pandemic modified the Residency Match process for fourth-year medical students. In-person away rotations were discouraged, interviews were virtual, and traditional factors used to rank programs were absent. Here, we compare survey results administered to both the 2020 and 2021 Match applicants to assess the influence of the pandemic on the RO Match process.Methods: An Institutional Review Board approved prospective cross-sectional study was conducted. The 2020 and 2021 RO Match applicants at a large RO program were invited to participate. Descriptive summary statistics were assessed.Results: The 2020 and 2021 Matches each had seventy-six applicants complete the survey with response rates of 54% and 57%, respectively. The two groups were predominantly white, cisgender male, single, and without children. While 11% of 2020 applicants did not complete away rotations, 45% of 2021 applicants did not. For 2021 Match applicants, 65% of away rotations were performed virtually while 51% were not for medical school credit. 84% of applicants were satisfied with virtual interviews and 72% felt cost savings were worth not having in-person interviews. While 49% of Match 2020 applicants spent >$5,000 in interview costs, 0% of the Match 2021 applicants did so, with 45% spending <$100. Post-interview communications from programs increased during the pandemic from 36% to 42% in 2020 Match and 2021 Match, respectively. While program culture was the most common factor influencing 2021 Match applicants program rankings, half of applicants did not gain a sense of program culture during virtual interviews.Conclusions: We find 2021 Match applicants completed fewer away rotations, were satisfied with virtual interviews/reduced costs, and did not gain a sense of program culture through virtual rotations/interviews despite it being the most important ranking factor reported. This study supports further exploration of virtual away rotations and virtual interviews moving forward beyond the pandemic.
View details for DOI 10.1016/j.adro.2021.100842
View details for PubMedID 34729444
Racial and Ethnic Disparities in Rates of Invasive Second Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawai'i.
JAMA network open
2021; 4 (10): e2128977
Importance: Women with ductal carcinoma in situ (DCIS) may develop a subsequent invasive second breast cancer (SBC). Understanding the association of racial and ethnic factors with the development of invasive SBC may help reduce overtreatment and undertreatment of women from minority groups.Objective: To evaluate risk factors associated with developing invasive ipsilateral SBC (iiSBC) and invasive contralateral SBC (icSBC) among women with an initial diagnosis of DCIS who are from racial and ethnic minority populations.Design, Setting, and Participants: This retrospective cohort study used deidentified data from the Hawai'i Tumor Registry of 6221 female Hawai'i residents aged 20 years or older who received a diagnosis of DCIS between January 1, 1973, and December 31, 2017. The 5 most populous ethnic groups were compared (Chinese, Filipino, Japanese, Native Hawaiian, and White). Data analysis was performed from 2020 to 2021.Exposures: Patient demographic and clinical characteristics and the first course of treatment.Main Outcome and Measures: The a priori study outcome was the development of invasive SBC. Logistic regression was used to identify factors associated with invasive SBC. Factors that were significant on unadjusted analyses were included in the adjusted models (ie, age, race and ethnicity, diagnosis year, DCIS histologic characteristics, laterality, hormone status, and treatment).Results: The racial and ethnic distribution of patients with DCIS across the state's most populous groups were 2270 Japanese women (37%), 1411 White women (23%), 840 Filipino women (14%), 821 Native Hawaiian women (13%), and 491 Chinese women (8%). Women of other minority race and ethnicity collectively comprised 6% of cases (n=388). A total of 6221 women (age range, 20 to ≥80 years) were included in the study; 4817 (77%) were 50 years of age or older, 4452 (72%) received a diagnosis between 2000 and 2017, 2581 (42%) had well or moderately differentiated histologic characteristics, 2383 (38%) had noninfiltrating intraductal DCIS, and 2011 (32%) were treated with mastectomy only. Of these 6221 women, 444 (7%) developed invasive SBC; 190 developed iiSBC (median time to SBC diagnosis, 7.8 years [range, 0.5-30 years]) and 254 developed icSBC (median time to SBC diagnosis, 5.9 years [range, 0.5-28.8 years]). On adjusted analysis, women who developed iiSBC were more likely to be younger than 50 years (adjusted odds ratio [aOR], 1.49; 95% CI, 1.08-2.06), Native Hawaiian (aOR, 3.28; 95% CI, 2.01-5.35), Filipino (aOR, 1.94; 95% CI, 1.11-3.42), Japanese (aOR, 1.58; 95% CI, 1.01-2.48), and untreated (aOR, 2.29; 95% CI, 1.09-4.80). Compared with breast-conserving surgery (BCS) alone, there was a decreased likelihood of iiSBC among women receiving BCS and radiotherapy (aOR, 0.45; 95% CI, 0.27-0.75), BCS and systemic treatment with or without radiotherapy (aOR, 0.40; 95% CI, 0.23-0.69), mastectomy only (aOR, 0.23; 95% CI, 0.13-0.39), and mastectomy and systemic treatment (aOR, 0.57; 95% CI, 0.33-0.96). Women who developed an icSBC were more likely to be Native Hawaiian (aOR, 1.69; 95% CI, 1.10-2.61) or Filipino (aOR, 1.70; 95% CI, 1.10-2.63). Risk of both iiSBC and icSBC decreased in the later years of diagnosis (2000-2017) compared with the earlier years (1973-1999).Conclusions and Relevance: This study suggests that Native Hawaiian and Filipino women who initially received a diagnosis of DCIS were more likely to subsequently develop both iiSBC and icSBC. Japanese women and younger women were more likely to develop iiSBC. Subpopulation disaggregation may help guide clinical treatment and screening decisions for at-risk subpopulations.
View details for DOI 10.1001/jamanetworkopen.2021.28977
View details for PubMedID 34668945
- Disaggregating Pacific Islanders and major Asian subpopulations to reveal hidden breast cancer disparities LIPPINCOTT WILLIAMS & WILKINS. 2021
Health care costs for adolescents and young adults with cancer: a Wisconsin community-based hospital study between 2005 and 2020.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
INTRODUCTION: Adolescents and young adults (AYA) with cancer are at risk of high cumulative healthcare system costs potentially associated with poor health and financial outcomes. Although this has been studied at academic centers, little data on AYA costs at community-based practices exist. The goals of this study were to understand direct health care costs for AYA patients, identify factors for high costs, and assess how total health care costs may relate to survival.METHODS: AYA patients (15-39years) treated at a community hospital in Wisconsin (USA) between 2005 and 2020 were identified. Patient demographics, cancer characteristics, therapies, support services, and all direct health care charges (including up to 1year prior to diagnosis to capture any diagnostic workup) were collected. Logistic and Cox proportional hazard regression models identified factors associated with high costs and survival, respectively.RESULTS: The 388 AYA patients had a median follow-up of 9years (97% survival). Most were 30-39years (62%), female (61%), white (95%), diagnosed early-stage (85%), and underwent surgery (83%). Complete health care costs were available for 233 patients (60%). Median total costs per patient were $123K (range, $73-$215K). On adjusted analysis, higher direct health care costs (>$125K) were associated with greater odds of hospital admissions (odds ratio [OR]=1.7, 95% CI=1.35-2.27), chemotherapy (OR=4.1, 95% CI=1.44-12.70), and breast cancer diagnosis (OR=3.8, 95% CI=1.07-14.70). Living farther from the hospital (OR=0.1, 95% CI=0.02-0.50), later year of diagnosis (OR=0.7, 95% CI=0.55-0.77), and uninsured/unknown insurance status (OR=0.1, 95% CI=0.01-0.57) were associated with decreased odds of having higher health care costs. On adjusted analysis, death was associated with greater odds of higher direct health care costs per $125K (hazards ratio [HR]=7.9, 95% CI=2.22-27.80) and radiation (HR=31.8, 95% CI=3.15-321) but lower odds of hormone therapy (HR=0.1, 95% CI=0.01-0.72) and later year of diagnosis (HR=0.3, 95% CI=0.12-0.60).CONCLUSION: High direct health care costs among AYA patients are associated with hospital admissions, chemotherapy, breast cancer diagnosis, hospital proximity, and earlier year of diagnosis. Death was associated with high direct health care costs, earlier years of diagnosis, and radiation therapy. Total health care costs in community-based hospitals should be considered in the context of AYA patients with cancer.
View details for DOI 10.1007/s00520-021-06584-0
View details for PubMedID 34564776
- Native Hawaiian and Other Pacific Islander Representation Among US Allopathic Medical Schools, Residency Programs, and Faculty Physicians. JAMA network open 2021; 4 (9): e2125051
Why an Increasing Number of Unmatched Residency Positions in Radiation Oncology? A Survey of Fourth-Year Medical Students
ADVANCES IN RADIATION ONCOLOGY
2021; 6 (5): 100743
The number of US fourth-year medical students applying to radiation oncology has decreased during the past few years. We conducted a survey of fourth-year medical students to examine factors that may be influencing the decision to pursue radiation oncology.An anonymous online survey was sent to medical students at 9 participating US medical schools.A total of 232 medical students completed the survey. Of the 153 students who stated they were never interested in radiation oncology, 77 (50%) reported never having been exposed to the specialty as their reason for not pursuing radiation oncology. The job market was the most commonly cited factor among students who said they were once interested in but ultimately chose not to pursue radiation oncology. Conversely, the recent low pass rates for board examinations and a perception of a lack of diversity within radiation oncology had the least influence.Despite discussion of potential measures to address this disquieting trend, there have been minimal formal attempts to characterize and address potential causes of a decreasing interest in radiation oncology. This study's data are consistent with previous research regarding the trend of decreased medical student interest in radiation oncology and may be used as part of ongoing introspective assessment to inform future change within radiation oncology.
View details for DOI 10.1016/j.adro.2021.100743
View details for Web of Science ID 000702562300002
View details for PubMedID 34466713
View details for PubMedCentralID PMC8385400
Away Rotations, Interviews, and Rank Lists: Radiation Oncology Residency Applicant Perspectives on the 2020 Match Process
ADVANCES IN RADIATION ONCOLOGY
2021; 6 (4): 100696
Using 2020 match applicants, the purpose of this study was to identify baseline applicant perspectives on the match process surveying (1) away rotations, (2) interview/postinterview communications, and (3) factors influencing applicant rank order lists.Applicants in the 2020 match cycle at a large radiation oncology (RO) residency program received a questionnaire covering demographics and the match process: away rotations, interview/postinterview communications, and ranking. Univariable and multivariable logistic regression analyses were used to identify factors associated with completing fewer away rotations.Of 141 surveys sent, 76 were completed, for a response rate of 54%. Most applicants were White, male, and matched into RO. One in 3 applicants did not have a home RO program. Most applicants completed 2 RO rotations (ie, a home rotation and an additional away rotation; range, 0-4 total rotations); RO rotations influenced the applicant rank order lists and the ultimate match result for 94% and 79% of applicants, respectively. Forty-seven percent of applicants reported being asked inappropriate questions during the interview (eg, parental or marital status). Applicants did not perceive a consistent message regarding postinterview communications from program directors. Most applicants were contacted postinterview. Interviews cost most applicants more than $5000. Thirty-seven percent of respondents reported submitting a letter of interest after the interview, hoping to improve their rank. When applying to programs, general reputation and location were the most common influential factors mentioned. When ranking programs, informal conversations with residents and program culture observations were the most common influential factors mentioned. Based on multivariable analysis, applicants who completed fewer RO rotations (including away rotations) had greater odds of matching to their home program (odds ratio [OR], 12.05; 95% CI, 1.27-206.69), lower odds of program location influencing where to apply (OR, 0.04; 95% CI, 0.003-0.37), and lower odds of the program's general reputation affecting their rank list (OR, 0.04; 95% CI, 0.001-0.47).The results suggest that medical students perceive away rotations as an important influencer of their match process. Although applicants and program directors both participate in postinterview communications, interactions with residents influence rank order lists. These data may serve as an up-to-date baseline to evaluate the influence of the COVID-19 pandemic on the RO match process.
View details for DOI 10.1016/j.adro.2021.100696
View details for Web of Science ID 000692613400036
View details for PubMedID 34113741
View details for PubMedCentralID PMC8170351
Metastasis-directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-resistant Prostate Cancer
EUROPEAN UROLOGY ONCOLOGY
2021; 4 (3): 447-455
Available therapies for castrate-resistant prostate cancer (CRPC) confer minimal survival advantage; thus, there is interest in metastasis-directed therapy (MDT) for oligometastatic or oligoprogressive disease to improve outcomes. Here, we describe outcomes of oligoprogressive CRPC treated with stereotactic ablative radiotherapy (SABR).To report outcomes of oligoprogressive CRPC treated with MDT using SABR.Patients with oligoprogressive CRPC were retrospectively evaluated, and outcomes following MDT were reported. Outcomes were additionally compared with oligoprogressive CRPC treated with change in systemic therapy alone.SABR to oligoprogressive lesions.Outcomes of interest were time to prostate-specific antigen (PSA) failure, time to next intervention (TTNI), distant metastasis-free survival (DMFS), and overall survival. Survival analysis was performed using the Kaplan-Meier method, and univariable analysis and multivariable analysis (MVA) were performed.A total of 68 patients were included. After MDT, median time to PSA recurrence, TTNI, and DMFS were 9.7, 15.6, and 10.8 months, respectively. A total of 112 lesions were treated, and the cumulative incidences of local failure at 12 and 24 months were 2.1% and 13.8%, respectively. Factors associated with the risk of local recurrence on univariable analysis were age (hazard ratio [HR] 1.07, p = 0.03) and Gleason grade group (HR 2.20, p = 0.07). Compared with change in systemic therapy alone (n = 52), MDT (n = 31) was associated with improved median time to PSA failure (9.7 vs 4.2 months, p = 0.066)), TTNI (14.9 vs 8.8 months, p = 0.025), and DMFS (12.7 vs 8.9 months, p = 0.045), and remained associated with improved outcomes on MVA.In a retrospective cohort of oligoprogressive CRPC patients, MDT was associated with favorable outcomes and improved cancer control as compared with change in systemic treatment alone. Future prospective trials are needed to confirm these findings.In this report, we retrospectively analyzed outcomes of patients with oligoprogressive castrate-resistant prostate cancer treated with radiation therapy to progressing lesions. Our results suggest that treatment of these lesions with radiation therapy can result in sustained periods of disease-free survival and might add benefit in addition to systemic therapy at the time of progression. These results need to be verified in a prospective trial to identify the optimal integration of radiation therapy into metastatic castrate-resistant prostate cancer.
View details for DOI 10.1016/j.euo.2020.05.004
View details for Web of Science ID 000656890300016
View details for PubMedID 32536574
View details for PubMedCentralID PMC7788526
The transactivation domain of TWIST1 is required for TWIST1-induced aggressiveness in non-small cell lung cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000641160600095
- Radiation Oncology Application and Match Patterns, Pre- and Post-SOAP (Supplemental Offer and Acceptance Program) from 2012 to 2020 PRACTICAL RADIATION ONCOLOGY 2021; 11 (2): 152-153
The Game Continues: Seeking Clarity in the Radiation Oncology Match.
Advances in radiation oncology
2021; 6 (2): 100627
Though the previous Gaming the Match agreement offered guidance to programs on how best to approach the Match process, guidance for applicants remains inconsistent. Here we review and propose guidelines by which the spirit of the Match may better be achieved for both program directors and applicants alike.
View details for DOI 10.1016/j.adro.2020.11.012
View details for PubMedID 33851062
- Navigating Native Hawaiian and Pacific Islander Cancer Disparities From a Cultural and Historical Perspective JCO ONCOLOGY PRACTICE 2021; 17 (3): 130-+
Patterns of Recurrence and Modes of Progression After Metastasis-Directed Therapy in Oligometastatic Castration-Sensitive Prostate Cancer
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2021; 109 (2): 387-395
Metastasis-directed therapy (MDT) is increasingly used in castration-sensitive oligometastatic prostate cancer because it prolongs progression-free survival (PFS) and androgen deprivation free survival. Here we describe patterns of recurrence and identify modes of progression after MDT using SABR.Two hundred fifty-eight patients with castration-sensitive oligometastatic prostate cancer (≤5 lesions at staging) were retrospectively identified from a multi-institutional database. Descriptive patterns of recurrence and modes of progression were reported. Other outcomes including median time to prostate-specific antigen (PSA) recurrence, time to next intervention, distant metastasis-free survival, overall survival, and biochemical PFS (bPFS) were reported. Survival analysis was performed using the Kaplan-Meier method, and multivariable analysis was performed.Median follow-up was 25.2 months, and 50.4% of patients received concurrent androgen deprivation. Median time to PSA recurrence was 15.7 months, time to next intervention was 28.6 months, distant metastasis-free survival was 19.1 months, and bPFS was 16.1 months. Two-year overall survival was 96.8%. On multivariable analysis, factors associated with bPFS included age (hazard ratio [HR], 1.03; P = .04), N1 disease at diagnosis (HR, 2.00; P = .02), M1 disease at diagnosis (HR, 0.44; P = .01), initial PSA at diagnosis (HR, 1.002; P = <.001), use of androgen deprivation therapy (HR, 0.41; P < .001), pre-SABR PSA (HR, 1.02; P = .01), and use of enhanced imaging for staging (HR, 2.81; P = .001). Patterns of progression favored an osseous component at recurrence; in patients initially treated to a bone lesion alone, the vast majority (86.5%) experienced a recurrence that included an osseous site. Patients treated initially to a nodal site alone tended to recur in a node only (64.5%); however, there was also a significant minority with an osseous component of recurrence at progression (32.3%). Modes of progressors were class I (patients with long term control [no recurrence ≥18 months after therapy]) occurring in 40.9%, class II (oligoprogressors [≤3 lesions at recurrence]) occurring in 36% (including 7.9% of patients with PSA recurrence but no metastatic disease), and class III (polyprogressors [>3 lesions]) occurring in 23.1% of patients.After MDT, the majority of patients have long-term control or oligoprogression (class I or II). Recurrence tended to occur in osseous sites. These findings, if validated, have implications for future integration of MDT and clinical trial design.
View details for DOI 10.1016/j.ijrobp.2020.08.030
View details for Web of Science ID 000607368300014
View details for PubMedID 32798608
View details for PubMedCentralID PMC7856169
Prostate Cancer Disparities in Risk Group at Presentation and Access to Treatment for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study With Disaggregated Ethnic Groups.
JCO oncology practice
We identified (1) differences in localized prostate cancer (PCa) risk group at presentation and (2) disparities in access to initial treatment for Asian American, Native Hawaiian, and Pacific Islander (AANHPI) men with PCa after controlling for sociodemographic factors.We assessed all patients in the National Cancer Database with localized PCa with low-, intermediate-, and high-risk disease who identified as Thai, White, Asian Indian, Chinese, Vietnamese, Korean, Japanese, Filipino, Hawaiian, Pacific Islander, Laotian, Pakistani, Kampuchean, and Hmong. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of (1) presenting at progressively higher risk group and (2) receiving treatment or active surveillance with intermediate- or high-risk disease, adjusting for sociodemographic and clinical factors.Among 980,889 men (median age 66 years), all AANHPI subgroups with the exception of Thai (AOR = 0.84 [95% CI, 0.58 to 1.21], P > .05), Asian Indian (AOR = 1.12 [95% CI, 1.00 to 1.25], P > .05), and Pakistani (AOR = 1.34 [95% CI, 0.98 to 1.83], P > .05) men had greater odds of presenting at a progressively higher PCa risk group compared with White patients (Chinese AOR = 1.18 [95% CI, 1.11 to 1.25], P < .001; Japanese AOR = 1.36 [95% CI, 1.26 to 1.47], P < .001; Filipino AOR = 1.37 [95% CI, 1.29 to 1.46], P < .001; Korean AOR = 1.32 [95% CI, 1.18 to 1.48], P < .001; Vietnamese AOR = 1.20 [95% CI, 1.07 to 1.35], P = .002; Laotian AOR = 1.60 [95% CI, 1.08 to 2.36], P = .018; Hmong AOR = 4.07 [95% CI, 1.54 to 10.81], P = .005; Kampuchean AOR = 1.55 [95% CI, 1.03 to 2.34], P = .036; Asian Indian or Pakistani AOR = 1.15 [95% CI, 1.07 to 1.24], P < .001; Native Hawaiians AOR = 1.58 [95% CI, 1.38 to 1.80], P < .001; and Pacific Islanders AOR = 1.58 [95% CI, 1.37 to 1.82], P < .001). Additionally, Japanese Americans (AOR = 1.46 [95% CI, 1.09 to 1.97], P = .013) were more likely to receive treatment compared with White patients.Our findings suggest that there are differences in PCa risk group at presentation by race or ethnicity among Asian American, Native Hawaiian, and Pacific Islander subgroups and that there exist disparities in treatment patterns. Although AANHPI are often studied as a homogenous group, heterogeneity upon subgroup disaggregation underscores the importance of further study to assess and address barriers to PCa care.
View details for DOI 10.1200/OP.21.00412
View details for PubMedID 34709962
- Healing and Health Equity for Asian American, Native Hawaiian, and Pacific Islander Populations. JAMA 2021; 326 (23): 2432-2433
Reducing Heart Dose with Protons and Cardiac Substructure Sparing for Mediastinal Lymphoma Treatment
INTERNATIONAL JOURNAL OF PARTICLE THERAPY
2020; 7 (1): 1-12
Electrocardiogram-gated computed tomography with coronary angiography can be used for cardiac substructure sparing (CSS) optimization, which identifies and improves avoidance of cardiac substructures when treating with intensity modulated radiotherapy (IMRT). We investigated whether intensity modulated proton therapy (IMPT) would further reduce dose to cardiac substructures for patients with mediastinal lymphoma.Twenty-one patients with mediastinal lymphoma were enrolled and underwent electrocardiogram-gated computed tomography angiography during or shortly after simulation for radiotherapy planning. Thirteen patients with delineated cardiac substructures underwent comparative planning with both IMPT and IMRT. Plans were normalized for equivalent (95%) target volume coverage for treatment comparison.Thirteen patients met criteria for this study. The median size of the mediastinal lymphadenopathy was 7.9 cm at the greatest diameter. Compared with IMRT-CSS, IMPT-CSS significantly reduced mean dose to all cardiac substructures, including 3 coronary arteries and 4 cardiac valves. Use of IMPT significantly reduced average whole-heart dose from 9.6 to 4.9 Gy (P < .0001), and average mean lung dose was 9.7 vs 5.8 Gy (P < .0001). Prospectively defined clinically meaningful improvement was observed in at least 1 coronary artery in 9 patients (69%), at least 1 cardiac valve in 10 patients (77%), and whole heart in all 13 patients.For patients with mediastinal lymphoma, IMPT-CSS treatment planning significantly reduced radiation dose to cardiac substructures. The significant improvements outlined in this study for proton therapy suggest possible clinical improvement in alignment with previous analyses of CSS optimization.
View details for DOI 10.14338/IJPT-20-00010.1
View details for Web of Science ID 000610832000001
View details for PubMedID 33094130
View details for PubMedCentralID PMC7574827
O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis.
AMER ASSOC CANCER RESEARCH. 2020: 59
View details for Web of Science ID 000531799600091
Electrocardiogram-Gated Computed Tomography with Coronary Angiography for Cardiac Substructure Delineation and Sparing in Patients with Mediastinal Lymphomas Treated with Radiation Therapy
PRACTICAL RADIATION ONCOLOGY
2020; 10 (2): 104-111
(1) Demonstrate feasibility of electrocardiogram-gated computed tomography with coronary angiography (E-CTA) in treatment planning for mediastinal lymphoma and (2) assess whether inclusion of cardiac substructures in the radiation plan optimization (CSS optimization) results in increased cardiac substructure sparing.Patients with mediastinal lymphomas requiring radiation therapy were prospectively enrolled in an observational study. Patients completed a treatment planning computed tomography scan and E-CTA in the deep inspiration breath hold position. Avoidance structures (eg, coronary arteries and cardiac valves) were created in systole and diastole and then merged into a single planning organ-at-risk volume based on a cardiac substructure contouring atlas. In the photon cohort, 2 volumetric modulated arc therapy plans were created per patient with and without CSS optimization. Dosimetric endpoints were compared.In the photon cohort, 7 patients were enrolled. For all 7 patients, the treating physician elected to use the CSS optimization plan. At the individual level, 2 patients had reductions of 10.8% and 16.2% of the right coronary artery receiving at least 15 Gy, and 1 had a reduction of 9.6% of the left anterior descending artery receiving 30 Gy. No other differences for coronary arteries were detected between 15 and 30 Gy. Conversely, 5 of 7 patients had >10% reductions in dose between 15 to 30 Gy to at least 1 cardiac valve. The greatest reduction was 22.8% of the aortic valve receiving at least 30 Gy for 1 patient. At the cohort level, the maximum, mean, and 5-Gy increment analyses were nominally similar between planning techniques for all cardiac substructures and the lungs.Cardiac substructure delineation using E-CTA was feasible, and inclusion in optimization led to modest improvements in sparing of radiosensitive cardiac substructures for some patients.
View details for DOI 10.1016/j.prro.2019.10.016
View details for Web of Science ID 000518851800015
View details for PubMedID 31783172
Biologics and 30-Day Postoperative Complications After Abdominal Operations for Crohn's Disease: Are There Differences in the Safety Profiles?
DISEASES OF THE COLON & RECTUM
2019; 62 (11): 1352-1362
The evidence regarding the association of preoperative biologic exposure and postoperative outcomes remains controversial for both antitumor necrosis factor agents and vedolizumab and largely unknown for ustekinumab.The purpose of this study was to determine differences in the rates of 30-day postoperative overall infectious complications and intra-abdominal septic complications among the 3 classes of biologic therapies as compared with no biologic therapy.This was a retrospective review.The study was conducted at an IBD referral center.Adult patients with Crohn's disease who received an antitumor necrosis factor, vedolizumab, ustekinumab, or no biologic therapy within 12 weeks of a major abdominal operation between May 20, 2014, and December 31, 2017, were included.Thirty-day overall postoperative infectious complications and intra-abdominal septic complications were measured.A total of 712 patients with Crohn's disease were included; 272 patients were exposed to an antitumor necrosis factor agents, 127 to vedolizumab, 38 to ustekinumab, and 275 to no biologic therapy within the 12 weeks before an abdominal operation. Patients exposed to a biologic were more likely to be taking a concurrent immunomodulator, but there was no difference in concurrent corticosteroid usage. The particular class of biologic was not independently associated with total overall infectious complications. Vedolizumab was associated with an increased rate of intra-abdominal sepsis on univariate analysis but not on multivariable analysis. Combination immunosuppression was associated with both an increased rate of overall postoperative infectious complications and intra-abdominal sepsis.The study was limited by its retrospective design and single-center data.The overall rate of total infectious complications or intra-abdominal septic complications was not increased based on preoperative exposure to a particular class of biologic. Rates increased with combination immunosuppression of biologic therapy with corticosteroids and previous abdominal resection. See Video Abstract at http://links.lww.com/DCR/B24. BIOLÓGICOS Y COMPLICACIONES POSTOPERATORIAS DE 30 DÍAS DESPUÉS DE LAS OPERACIONES ABDOMINALES PARA LA ENFERMEDAD DE CROHN: ¿EXISTEN DIFERENCIAS EN LOS PERFILES DE SEGURIDAD?:: La evidencia sobre la asociación de la exposición biológica preoperatoria y los resultados postoperatorios sigue siendo controvertida controversial tanto para los agentes del factor de necrosis tumoral (anti-TNF) como para el vedolizumab, y en gran parte desconocida para el ustekinumab.Determinar las diferencias en las tasas de complicaciones infecciosas generales postoperatorias de 30 días y complicaciones sépticas intraabdominales entre las tres clases de terapias biológicas en comparación con ninguna terapia biológica.Revisión retrospectiva.centro de referencia de la enfermedad inflamatoria intestinal.Pacientes adultos con enfermedad de Crohn que recibieron un factor de necrosis antitumoral, vedolizumab, ustekinumab o ningún tratamiento biológico dentro de las 12 semanas de una operación abdominal mayor entre el 5/20/2014 y el 12/31/2017.Complicaciones infecciosas postoperatorias generales de 30 días, complicaciones sépticas intraabdominales.Se incluyeron setecientos doce pacientes con enfermedad de Crohn; 272 pacientes fueron expuestos a un anti-TNF, 127 a vedolizumab, 38 a ustekinumab y 275 a ninguna terapia biológica dentro de las 12 semanas previas a una operación abdominal. Los pacientes expuestos a un producto biológico tenían más probabilidades de tomar un inmunomodulador concurrente, pero no hubo diferencias en el uso simultáneo de corticosteroides. La clase particular de productos biológicos no se asoció de forma independiente con las complicaciones infecciosas totales. Vedolizumab se asoció con una mayor tasa de sepsis intraabdominal en el análisis univariable, pero no en el análisis multivariable. La inmunosupresión combinada se asoció tanto con una mayor tasa de complicaciones infecciosas postoperatorias generales como con sepsis intraabdominal.Diseño retrospectivo, datos de centro único.La tasa general de complicaciones infecciosas totales o complicaciones sépticas intraabdominales no aumentó en función de la exposición preoperatoria a una clase particular de productos biológicos. Las tasas aumentaron con la combinación de inmunosupresión de la terapia biológica con corticosteroides y resección abdominal previa. Vea el Resumen del Video en http://links.lww.com/DCR/B24.
View details for DOI 10.1097/DCR.0000000000001482
View details for Web of Science ID 000490158900014
View details for PubMedID 31567927
Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity and outcomes in the modern era
LEUKEMIA & LYMPHOMA
2020; 61 (2): 298-308
One-in-five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT). Given bleomycin-omission data with negative interim-PET, we assessed changes in BPT statistics. We retrospectively evaluated 126 ABVD-treated HL patients for overall survival (OS), progression-free survival (PFS), BPT factors, and management. Forty-seven patients developed BPT with 17% BPT-mortality. In univariable analysis, OS was negatively impacted by BPT (HR = 3.6, 95%CI = 1.2-10.6), but not bleomycin-omission (HR = 1.3, 95%CI = 0.5-3.7). In multivariable analysis, BPT was not associated with OS (HR = 3.0, 95%CI = 0.9-9.9). BPT patients were older (46 y vs 33 years) and received less bleomycin (107 vs 215 units) compared to non-BPT patients. BPT was managed primarily with bleomycin-omission. "Recent Era" patients had lower BPT rates (28% vs 48%), mortality (10% vs 21%), and bleomycin doses (7 vs 12 doses), yet higher bleomycin-omission in the absence of the BPT (59% vs 8%) compared to "Early Era". Our data suggest BPT continually impacts OS in ABVD-treated HL patients, however management is changing.
View details for DOI 10.1080/10428194.2019.1663419
View details for Web of Science ID 000486469300001
View details for PubMedID 31517559
Cancer Therapeutic Strategies and Treatment Resistance
PRINCIPLES OF CLINICAL CANCER RESEARCH
View details for Web of Science ID 000485118400009
O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis
JOURNAL OF CLINICAL INVESTIGATION
2018; 128 (11): 4924–37
Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked β-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.
View details for PubMedID 30130254
TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis
2017; 77 (12): 3181-3193
TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181-93. ©2017 AACR.
View details for DOI 10.1158/0008-5472.CAN-16-2797
View details for Web of Science ID 000403328500008
View details for PubMedID 28484075
View details for PubMedCentralID PMC5489316
Therapeutic Targeting of Epithelial Plasticity Programs: Focus on the Epithelial-Mesenchymal Transition
KARGER. 2017: 114-127
Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into 3 groups: (1) extracellular inducers of EMT, (2) the transcription factors that orchestrate the EMT transcriptome, and (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT, such as the signal transduction pathways TGFβ, EFGR, and Axl-Gas6. We emphasize in more detail pathways that we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways, and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only 1 EMT-related process will be unsuccessful or only transiently successful. We suggest that with greater understanding of epithelial plasticity regulation, such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes.
View details for DOI 10.1159/000447238
View details for Web of Science ID 000394922500006
View details for PubMedID 28214899
View details for PubMedCentralID PMC5375029
Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated neoplastic Phenotypes
FRONTIERS IN ONCOLOGY
2016; 6: 85
The epithelial-mesenchymal transition (EMT) is a highly conserved program necessary for orchestrating distant cell migration during embryonic development. Multiple studies in cancer have demonstrated a critical role for EMT during the initial stages of tumorigenesis and later during tumor invasion. Transcription factors (TFs) such as SNAIL, TWIST, and ZEB are master EMT regulators that are aberrantly overexpressed in many malignancies. Recent evidence correlates EMT-related transcriptomic alterations with metabolic reprograming in cancer. Metabolic alterations may allow cancer to adapt to environmental stressors, supporting the irregular macromolecular demand of rapid proliferation. One potential metabolic pathway of increasing importance is the hexosamine biosynthesis pathway (HBP). The HBP utilizes glycolytic intermediates to generate the metabolite UDP-GlcNAc. This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates. Recent reports in the field of glycobiology have cultivated great curiosity within the cancer research community. However, specific mechanistic relationships between the HBP and fundamental pathways of cancer, such as EMT, have yet to be elucidated. Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell-cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs. Here, we outline some of the basics of the HBP and putative roles the HBP may have in driving EMT-related cancer processes. With novel appreciation of the HBP's connection to EMT, we hope to illuminate the potential for new therapeutic targets of cancer.
View details for DOI 10.3389/fonc.2016.00085
View details for Web of Science ID 000374216600001
View details for PubMedID 27148477
View details for PubMedCentralID PMC4834358
Ganetespib radiosensitization for liver cancer therapy
CANCER BIOLOGY & THERAPY
2016; 17 (4): 457–66
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33-1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.
View details for DOI 10.1080/15384047.2016.1156258
View details for Web of Science ID 000375583500016
View details for PubMedID 26980196
View details for PubMedCentralID PMC4910914
- Snai1 accelerates Kras driven lung tumorigenesis by overcoming oncogene-induced senescence AMER ASSOC CANCER RESEARCH. 2015
Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells
2015; 17 (1): 16-31
The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice.
View details for DOI 10.1016/j.neo.2014.10.009
View details for Web of Science ID 000348458300002
View details for PubMedID 25622896
View details for PubMedCentralID PMC4309734
Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity
INTERNATIONAL JOURNAL OF ONCOLOGY
2014; 45 (1): 219-226
Peroxiredoxin (Prdx) proteins are thiol-specific antioxidants that protect cells from oxidative stress in many normal and disease states. There are six Prdx proteins expressed in mammals, each with a characteristic tissue expression, subcellular distribution and substrate specificity. Recent studies have revealed elevated Prdx levels in many cancers, suggesting a protective role for these proteins in cancer cell survival. The present study is the first to investigate the function of all six Prdx proteins in the MCF-7 breast cancer cell line. We show that these cells have both higher resistance to doxorubicin-induced toxicity and significantly elevated Prdx levels, compared to the non-cancer MCF-10A cells. Using transient siRNA transfections, we show that Prdx3 suppression leads to decreased MCF-7 cell survival in the absence of doxorubicin. We further demonstrate that individual suppression of four of six of the Prdx proteins leads to increased doxorubicin-induced toxicity by apoptosis. Finally, we show that clonal selection of a doxorubicin-resistant MCF-7 subline by 2-week culture in 0.1 µM doxorubicin resulted in a marked elevation in the expression of several Prdx proteins. Together, these data reveal a protective function for peroxiredoxins in MCF-7 cell survival, and suggest that Prdx overexpression in breast cancer may play a role in doxorubicin-resistance in these, and possibly other, breast cancer cells. This study is the first to investigate the function of the entire Prdx family in a breast cancer cell line.
View details for DOI 10.3892/ijo.2014.2398
View details for Web of Science ID 000336881600024
View details for PubMedID 24789097
Peroxiredoxin Overexpression in MCF-7 Breast Cancer Cells and Regulation by Cell Proliferation and Oxidative Stress
2013; 31 (6): 374-384
Peroxiredoxins are thiol-specific antioxidant proteins that protect cells from ROS-induced cell death and are elevated in several cancers. We found that five of the six mammalian peroxiredoxins are overexpressed in MCF-7 breast cancer cells at the mRNA and protein levels, compared to noncancerous MCF-10A cells. Inhibition of MCF-7 proliferation reduced the levels of several peroxiredoxins. In contrast, all six proteins were strongly and transiently induced in MCF-7 cells by H₂O₂. These data suggest that coordinate overexpression of peroxiredoxins may be an important cancer cell adaptation, and that these proteins can be regulated by cell proliferation and oxidative stress.
View details for DOI 10.3109/07357907.2013.802798
View details for Web of Science ID 000320866800002
View details for PubMedID 23758190
Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma
2013; 8 (6): e65726
Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.
View details for DOI 10.1371/journal.pone.0065726
View details for Web of Science ID 000321099000098
View details for PubMedID 23762417
View details for PubMedCentralID PMC3675179
Regeneration in the Hemichordate Ptychodera flava
2010; 27 (2): 91-95
When the body of P. flava is severed, the animal has the ability to regenerate its missing anterior or posterior as appropriate. We have focused on anterior regeneration when the head and branchial regions are severed from the body of the worm. After transection, the body wall contracts and heals closed in 2 to 3 days. By the third day a small blastema is evident at the point of closure. The blastema grows rapidly and begins the process of differentiating into a head with a proboscis and collar. At 5 days the blastema has increased greatly in size and differentiated into a central bulb, the forming proboscis, and two lateral crescents, the forming collar. Between 5 and 7 days a mouth opens ventral to the differentiating blastema. Over the next few days the lateral crescents extend to encircle the proboscis and mouth, making a fully formed collar. By 10 to 12 days a new head, sized to fit the worm's body, has grown attached to the severed site. At about this time the animal regains apparently normal burrowing behavior. After the head is formed, a second blastema-like area appears between the new head and the old body and a new branchial region is inserted by regeneration from this blastema over the next 2 to 3 weeks. The regenerating tissues are unpigmented and whitish such that in-situ hybridization can be used to study the expression of genes during the formation of new tissues.
View details for DOI 10.2108/zsj.27.91
View details for Web of Science ID 000274061600005
View details for PubMedID 20141413